The Research Review

A new study suggests there may not be any clinical benefits to administering NTG to treat chest pain caused by myocardial ischemia

NTG Case Review: Medic 8 and Engine 14 are caring for a 57-year-old male with a chief complaint of crushing, substernal chest pain. The pain, rated as an 8 on a 1-10 scale, began about 15 minutes ago at rest, and is without other complaints.

Because the patient’s pulse oximetry values are above 94 percent, the firefighters do not administer oxygen. While placing pads on the patient’s chest for electrocardiogram (ECG) acquisition, Medic Davis administers four baby aspirin and directs the patient to chew the tablets before swallowing. The 12-lead ECG reveals ST-segment elevation myocardial infarction (STEMI) in the inferior leads.

Medic Rodgers reaches for the nitroglycerin (NTG) spray, but Davis says he would like to wait before administering the drug. The crew quickly moves the patient to the ambulance, activates a STEMI alert, and begins transport to the receiving facility.

This study suggests that hemodynamically stable patients with inferior wall STEMI have no greater risk of hypotensive episodes following NTG administration than patients with STEMI in other areas of heart muscle. (Photo/US Navy)

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During transport, Davis establishes intravenous access on the third attempt. Davis then acquires a right-sided, 12-lead ECG, which suggests right ventricular involvement. Instead of giving NTG, Davis administers intravenous fentanyl as the ambulance backs into the dock at the hospital.

One the way back to the station, Rodgers asks why Davis did not want to give NTG while in the patient’s house. Davis says he remembered a continuing education instructor once saying that giving NTG to inferior wall infarctions was dangerous because of the possibility of right ventricular involvement.

NTG study review

Researchers in Canada examined whether it was more dangerous for prehospital personnel to administer NTG to patients with inferior-wall STEMI than to those with STEMI in any other location [1]. The sample group for the comparison included adults with a chief complaint of chest pain presumed by the medics to be of cardiac origin. Standing order protocol in the EMS system allowed medics to administer sublingual NTG 0.4 mg/spray every five minutes as long as the patient remained hemodynamically stable, which was defined as systolic blood pressure (SBP) ≥ 100 mmHg and a heart rate between 50 and 150 beats per minute. NTG was contraindicated in the system if the SBP and heart rate did not fall within the accepted parameters, if the patient was pregnant, if the chest pain was trauma-related, if the patient was allergic to nitrates or if the patient had used erectile dysfunction medications recently.

The medics in this study were trained to acquire but not interpret the 12-lead ECG. Instead, the medics used the computerized interpretation provided by the monitor. The decision to administer NTG was based on the presence of cardiac chest pain and not on infarction territory, i.e., NTG was not withheld in the presence of inferior STEMI.

The primary outcome variable was a fall in SBP below 90 mmHg after NTG administration. The researchers analyzed two secondary outcome variables. First, researchers examined whether NTG administration resulted in a reduction of SBP by 30 mmHg or more. Next, the team subdivided the inferior STEMI group into those thought to be involving the right ventricle (greater ST elevation in lead III than in lead II or ST elevation in V1) and those presumed not to involve the right ventricle. These two groups were compared to see if one had a greater risk of hypotension following NTG administration.

Nitroglycerine study results

During the 29-month study period, there were 1,466 STEMI cases. Slightly more than half (56 percent) received NTG according to protocol. NTG was contraindicated in the remaining 44 percent. Of the patients who received NTG (n = 821), 16 had incomplete data and were excluded from the analysis.

Of the remaining 805 cases, the computerized 12-lead interpretation determined 466 patients (58 percent) had inferior STEMIs while 339 (42 percent) had non-inferior STEMIs. The inferior STEMI group had a higher incidence of initial heart rate, diastolic blood pressure, diabetes mellitus, dyslipidemia, and previous history of coronary artery disease. The incidence of hypotension (SBP < 90 mmHg) following NTG administration was not significantly different between the two groups, 8.2 percent vs. 8.9 percent, respectively, p = 0.73. There was also no significant difference in the incidence of severe SBP drop (≥ 30 mmHg) following NTG administration between the two groups, 23.4 percent vs. 23.9 percent, respectively, p = 0.87.

In the analysis involving physician-interpreted STEMI, there was also no difference in the incidence of hypotension following NTG administration between those with inferior STEMI and those with STEMI in other myocardial territories, 8.9 percent vs. 8.3 percent, respectively, p = 0.80.

In the comparison between inferior STEMI and inferior STEMI thought to involve the right ventricle, the authors report no difference in hypotension (systolic BP < 90 mmHg) following NTG administration, although the authors did not report the statistics.

What NTG results means for you

This study suggests that hemodynamically stable patients with inferior wall STEMI have no greater risk of hypotensive episodes following NTG administration than patients with STEMI in other areas of heart muscle. Further, in the subgroup of patients who suffered an inferior wall STEMI, those with ECG evidence of right ventricular involvement were no more likely to suffer 30 mmHg or greater reductions in SBP following NTG administration than those without.

For over a century, physicians have used NTG to treat chest pain caused by myocardial ischemia. NTG causes vascular smooth muscle cells to release a chemical called nitric oxide [2]. Nitric oxide, through a variety of chemical reactions, promotes vasodilation [2] and helps inhibit platelet aggregation [3], both of which may be physiologically beneficial in acute coronary ischemic episodes.

Despite these benefits, the American Heart Association (AHA) acknowledges limited clinical benefits associated with NTG administration and a lack of conclusive evidence to support its routine use in the management of AMI [4]. More recently, an evidence review conducted by the EMS Medical Directors Association of California found insufficient evidence to support a clinical benefit or harm in using NTG for the prehospital treatment of chest pain [5]. The use of NTG in the management of ACS was not reviewed in 2015 by the International Liaison Committee on Resuscitation (ILCOR) or the AHA [6].

Case reports describe significant reduction in SBP following sublingual NTG administration in patients with ischemic chest pain [7,8]. When administered by EMS personnel to treat chest pain thought to be caused by myocardial ischemia, adverse event rates are rare, ranging from 0.7 percent to 1.3 percent [8,9]. Unfortunately, there are still no reliable predictors for determining which patient may suffer an adverse event [10].

A common restriction to NTG use is for patients with evidence of inferior STEMI, especially if the infarction may involve the right ventricular wall. Inferior wall infarctions may account for about half of all infarctions [11]. Right ventricular involvement complicates the management of between one-fourth and one-third of patients with acute inferior wall infarction [12,13], although others estimate the incidence to be much higher [14].

NTG affects both ventricles by reducing both afterload and preload [15]. Right ventricular infarction may reduce preload and subsequent cardiac output, which can be further reduced by the administration of NTG [16]. An often-cited study in support of this hemodynamic response to NTG was limited by a retrospective design and the simultaneous administration of calcium channel blockers to many of the study participants [17].

Despite the lack of strong evidence, AHA warns that NTG should be used with caution (if at all) in patients with ECG evidence of inferior wall STEMI when one suspects right ventricular involvement [4]. However, when right ventricular infarction is confirmed, NTG is generally contraindicated [4]. The results of this study challenge those concerns.

Limitations of the present NTG study

Before EMS agencies begin throwing NTG into the trash, one must consider the results of this study in context. First, this was a retrospective analysis, which means the medics responded to calls as they normally do, and the researchers later discovered eligible cases through chart review. The very nature of the retrospective design prohibits anyone from controlling (and sometimes identifying) variables that might have influenced the outcome. For that type of control, one would need to conduct a randomized and controlled trial. That will probably never happen due to ethical concerns.

Next, during the study period, there were 1,466 STEMI cases, yet only 821 patients (56 percent) received NTG (complete data was only available for 805 patients). The researchers excluded the remaining 46 percent cases because each had one or more exclusionary characteristics. These included STEMI that did not produce chest pain (silent MI), chest pain no longer present on EMS arrival due to patient-administered NTG, or some other contraindication to NTG administration. One can only speculate about the results if everyone had received NTG. Consequently, it is problematic to draw strong conclusions when half of the study population is excluded.

Finally, there is a statistical procedure known as a power analysis that helps researchers determine how many patients are needed to find a difference between two groups, if a difference truly exists. One of the values used in that calculation is the rate of hypotensive episodes expected to occur following NTG administration. The researchers used 15 percent, a value taken from the frequently cited study previously mentioned [17]. Based on this rate, the analysis indicated the need for 725 patients to find a 6 percent relative difference between the two groups. However, the actual hypotensive episodes rate in this study was only 8.2 percent. Substituting that value into the formula returned the need for 38,000 patients to demonstrate the same relative difference (6 percent) between the groups. Thus, this study did not have enough participants to find that difference, if a difference truly exists.

NTG study summary

The concerns about NTG administration to patients with inferior wall MI may be overstated. This study suggests that EMS personnel who are not trained in ECG interpretation and do not have the authorization to establish IV access can still administer NTG safely to hemodynamically stable patients with STEMI, regardless of the infarction territory. This study also suggests that hemodynamically stable infarctions involving the right ventricle are at no greater risk of significant reductions in SBP following NTG administration than inferior wall infarctions not involving the right ventricle.

The author has no financial interest, arrangement or direct affiliation with any corporation that has a direct interest in the subject matter of this presentation, including manufacturer(s) of any products or provider(s) of services mentioned.

Divakaran, S., & Loscalzo, J. (2017). The role of nitroglycerin and other nitrogen oxides in cardiovascular therapeutics. Journal of the American College of Cardiology, 70(19), 2393-2410. doi:10.1016/j.jacc.2017.09.106

About the author

Kenny Navarro is an Assistant Professor in the Department of Emergency Medicine at the University of Texas Southwestern Medical School at Dallas. He also serves as the AHA Training Center Coordinator for Tarrant County College. Mr. Navarro serves as an Emergency Cardiovascular Care Content Consultant for the American Heart Association, served on two education subcommittees for NIH-funded research projects, as the Coordinator for the National EMS Education Standards Project, and as an expert writer for the National EMS Education Standards Implementation Team. Send correspondence concerning any articles in this section to Kenneth W. Navarro, The University of Texas Southwestern Medical School at Dallas, 5323 Harry Hines Blvd MC 8890, Dallas, Texas 75390-8890, or e-mail kenny.navarro@ems1.com.

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